Cancer is a disorder characterized by uncontrolled proliferation and spread of abnormal cells. These abnormal cells can create expansive masses, spread to vital organs and eventually cause patient death. Cancer affects people worldwide.
Traditional approaches to treatment of abnormal cells proliferation include surgery, chemotherapy, radiotherapy, and the like, as well as combinations thereof. Surgery is not always an option due to tumor size or location, and/or advanced metastasis. Additionally, surgery might not completely remove the neoplastic tissue. Radiation therapy can often elicit serious side effects. Chemotherapy typically involves use of one or more compounds that inhibit cancer cell growth. Unfortunately, most known anticancer drugs have limited selectivity for cancer and are inherently toxic to both cancer and normal tissues. They also can cause significant side effects, including hair loss, suppression of hematopoesis, and nausea, etc. Depending on the general health of a patient, such side effects can preclude the administration of chemotherapy, or, at least, be extremely unpleasant and uncomfortable for the patient and severely decrease quality of the remaining life of cancer patients.
The drug discovery of new anticancer agents has recently moved from cell-based assay to a more focused in vitro approach on well characterized, isolated and transfection assisted expressed proteins of druggable targets. The transition from cytotoxic chemotherapy to molecularly targeted cancer drug discovery and development has resulted in an increasing number of successful therapies that have impacted the lives of a large number of cancer patients. The ABL inhibitor imatinib is generally regarded as a trail blazer drug that most impressively validated the concept of designing small molecule therapeutics to treat a defined patient population in this case chronic myeloid leukaemia in which the malignancy is driven by the BCR-ABL translocation and for which the improvement in survival has been dramatic (Druker, S. et al., N. Engl. J. Med. 2006 (355) 2408-2417). However, despite the considerable progress made with the new molecularly targeted therapies, several cancers seem to remain naturally resistant to the clinical use of kinase inhibitors or the molecularly targeted therapies are not really relevant (e.g. hepatocellular carcinoma and pancreas cancer). Moreover, the molecular understanding and the molecular description of cellular transformation, cancer growth, cancer microenvironment and metastasis evolution is still remain in constant development, with for example the description of the cancer stem cells (CSCs) concept or tumor initiating cells (TICs).
In 2013, the estimated number of liver cancers was 559,000 in men and 233,000 in women, which is comprehensive of the dominant hepatocarcinoma (HCC); hepatoblastoma and sarcoma. The estimated number of deaths due to this tumor was 554,000 and 254,000 respectively. Worldwide liver cancer stands at the second leading cause of cancer in men and the fifth in women with a median survival of 7.2 month (Global burden of cancer 2013 JAMA Oncol 2015 (1) 505-527). In spite of successful approval and wide application of sorafenib (SOC), the prognosis for patients with advanced hepatocellular carcinoma (HCC) remains poor. In recent years, highly tumorigenic sub-populations of cancer cells named Cancer Stem Cells (CSCs) have been implicated in post-treatment tumor recurrence. Indeed, CSCs are resistant to chemotherapy, and they have the ability to regenerate all the cell type within the tumor. For this reason, innovative drugs with original mechanism of action and could tackle CSCs would likely improve cancer treatment of patients.
In this context, we decided to take into account the whole cell compartment and a cellular culture environment with the development of an unbiased phenotypic cellular screening assay.
Accordingly, in view of the above considerations, it is seen that a constant need exists for active compounds that could help preventing and treating neoplastic and non-neoplastic proliferative diseases, such as cancer with either improved effect or reduced side effects.
In particular, a need exists for such active compounds that could help addressing the problems of cancer resistance.